Effects of a cannabinoid receptor (CB) 1 antagonist AM251 on behavioral sensitization to nicotine in a rat model of novelty-seeking behavior: correlation with hippocampal 5HT.
BACKGROUND
There are marked individual differences in the efficacy of mainstream nicotine cessation agents in preventing relapse. A rat model of novelty-seeking phenotype was reported to have predictive value for psychostimulant taking behavior where locomotor reactivity to novelty is used to rank high (HR, highest 1/3) versus low (LR, lowest 1/3) responsiveness to novelty in outbred rats. We tested the hypothesis that a cannabinoid receptor (CB) 1 antagonist that is in clinical trials for smoking cessation may reverse behaviorally sensitizing effects of nicotine in HRs and repeated nicotine-induced elevations in hippocampal 5HT.


METHODS
Adolescent LRHR rats underwent intermittent behavioral sensitization to nicotine regimen with or without a CB1 receptor antagonist AM251 or bupropion treatment following nicotine training during 1 week of nicotine-free period. Expression of behavioral sensitization to nicotine was assessed in response to a low-dose nicotine challenge. Using the same sensitization regimen and therapeutic treatments, hippocampal 5HT levels were measured via in vivo microdialysis in response to the nicotine challenge.


RESULTS
HR but not LR animals showed behavioral sensitization to a low-dose nicotine challenge following intermittent nicotine training and 1 week of injection-free period. AM251 (5 mg/kg, i.p.) but not bupropion administration during injection-free period successfully reversed locomotor sensitization to nicotine challenge in HRs. AM251 treatment also reversed nicotine-induced elevations in extracellular 5HT in the HR hippocampal hilus.


CONCLUSIONS
These data suggest that CB1 antagonists may prevent locomotor sensitization to nicotine and reverse nicotine-induced elevations in hippocampal 5HT in high novelty seekers.
Bhatti
Amrinder S
AS
Department of Basic Biomedical Sciences, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, 33431, USA.
Aydin
Cigdem
C
Oztan
Ozge
O
Ma
Zhiyuan
Z
Hall
Penny
P
Tao
Rui
R
Isgor
Ceylan
C
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016642:Bupropion / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D023421:Models, Animal; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D016540:Smoking Cessation / Q000379:methods*
D018722:Nicotinic Agonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D016642:Bupropion; D012701:Serotonin; C103505:AM 251; D009538:Nicotine